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Purpose: The combination of ionizing radiation with the pro-apoptotic TRAIL receptor antibody lexatumumab has been shown to exert considerable synergistic apoptotic effects in vitro and in short term growth delay assays. To clarify the relevance of these effects on local tumour control long-term experiments using a colorectal xenograft model were conducted. Materials and methods: Colo205-xenograft bearing NMRI (nu/nu) nude mice were treated with fractionated irradiation (5× 3 Gy, d1-5) and lexatumumab (0.75 mg/kg, d1, 4 and 8). The tumour bearing hind limbs were irradiated with graded single top up doses at d8 under normoxic (ambient) and acute hypoxic (clamped) conditions. Experimental animals were observed for 270 days. Growth delay and local tumour control were end points of the study. Statistical analysis of the experiments included evaluation of tumour regrowth and local tumour control. Results: Combined treatment with irradiation and lexatumumab led to a pronounced tumour regrowth-delay when compared to irradiation alone. The here presented long-term experiments revealed a highly significant rise of local tumour control for normoxic (ambient) (p = 0. 000006) and hypoxic treatment (p = 0. 000030). Conclusion: Our data show that a combination of the pro-apoptotic antibody lexatumumab with irradiation reduces tumour regrowth and leads to a highly increased local tumour control in a nude mouse model. This substantial effect was observed under ambient and more pronounced under hypoxic conditions. related apoptosis inducing ligand) receptor 2 (TRAIL-R2) Background Lexatumumab is a fully human agonistic antibody with a induced apoptosis. Although TRAIL-R2 stimulation alone distinct tumour cell specifity via activation of TRAIL (TNF- is highly effective in a wide range of cancer cell lines, effi- Page 1 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:49 http://www.ro-journal.com/content/4/1/49 cacy can be increased by combination with other gyro- Materials and methods static drugs (for review see ). We have already shown Animals and tumours Immunodeficient NMRI-(nu/nu)-nude mice were pur- that a combined treatment with TRAIL and irradiation exerts highly synergistic effects regarding apoptosis induc- chased from a specific pathogen free colony at the Univer- tion. This enhanced efficacy was detectable in various sity of Essen (Germany) at the age of 4-6 weeks. Animals solid tumour cell lines and lymphoid tumour cells[2,3]. were kept in an individually ventilated cage rack system (Techniplast, Italy) and fed with sterile high calorie labo- Since discovery of TRAIL and its receptors in 1997 a panel ratory food (Sniff, Germany). Drank water was supple- of agonistic antibodies for TRAIL-receptors R1 and R2 mented by chlorotetracycline and potassium sorbate have been developed and tested in clinical phase I and II acidified to a pH of 3.0 with hydrochloric acid. trials [4-18]. However, up to now only little data are avail- able concerning interaction of agonistic TRAIL receptor The Colo205 tumour cell line (established from a colorec- antibodies and irradiation ([7,19,20]. Besides our recently tal adenocarcinoma) was acquired from ATCC (Bethesda, published report no data on experiments with a combina- MD, USA). In NMRI-(nu/nu)-nude mice Colo205 cells tion of a fully human TRAIL receptor antibody and irradi- form solid, roundly shaped tumours without indication ation have been published. for metastasis. Combining mapatumumab or lexatumumab with irradi- Transplantation and experimental design ation, we have demonstrated that this combination exerts Tumour lumps of about 2 mm diameter from a source strong additive and synergistic effects on apoptosis induc- tumour were implanted subcutaneously into the right tion in vitro and in short-term growth delay experi- hind limb of 6-10 week old animals. Approximately 2-3 ments. However, to proof that induction of apoptosis weeks after transplantation tumour growth was measura- evidently translates into definitive tumour stem cell erad- ble. Tumour size was quantified with calipers in two per- ication long-term experiments with local tumour control pendicular diameters. The tumour volume (V) was as primary endpoint might provide a reliable model for calculated as V = (a × b )/2, where a and b are the long axis clinical potency [22-26]. and the short axis, respectively. Scoring of tumour sizes took place three times per week before start of treatment. Therefore, we decided to perform long-term experiments Body weight was monitored once a week. in a nude mouse xenograft model. As radiation sensitivity becomes affected by limiting intratumoural hypoxia we The median tumour volume at the start of experiments run experiments under both ambient and hypoxic condi- was 116 ± 31 mm . Animals were randomly allocated to tions to mimic realistic tumour conditions. 24 treatment arms (scheme see Figure 1): lexatumumab at day 1, 4 and 8 (0.75 mg/kg body weight intraperitoneally Taken together, our experimental series was designed to (i.p.)) alone, fractioned radiotherapy (5 × 3 Gy within five confirm the striking principle that radiation mediated subsequent days) alone. Single dose top up irradiations TRAIL sensitization effectively increases long-term local (0, 10.0, 14.5, 21.0, 30.4, 44.2 Gy) were performed on day tumour control. 8. Combined treatment was performed at day 1, 4 and 8 with lexatumumab (0.75 mg/kg) (figure 1). Control ani- graded top up dose (0-44,2 Gy) lexatumumab (0.75 mg/kg)/ θθ ±±±± irradiation d1 d4 d5 d8 d270 E Figure 1 xperimental design Experimental design. Small bolt = fractionated irradiation at d 1-5, large bolt = graded top up doses 0-44.2 Gy (under ambi- ent/hypoxic conditions, depending on stratification), small arrowhead: application of lexatumumab (0.75 mg/kg body weight), d = day. Page 2 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:49 http://www.ro-journal.com/content/4/1/49 mals were treated only with an i.p. injection of medium Figure 2 shows a chronological sequence of the impressive without antibody or irradiation. tumour regression after treatment with lexatumumab (0.75 mg/kg) for one test animal, exemplarily. Obviously, To minimize toxic side effects and to apply high irradia- tumour growth reduction started after the second applica- tion doses in an easy comparable, time saving schedule we tion i.p., already. However, lacking consolidating irradia- choose a combination of fractionated and graded single tion in this example tumour regrowth is evident four high dose (top up) irradiation. 3 Gy single dose was cho- weeks after start of treatment. sen for fractionated irradiation based on previous experi- ments (Marini et al., Oncogene 2006). Fractionated However, combination of very low doses of irradiation irradiation of tumours was applied in inhalation (Isoflu- with lexatumumab led to an unexpected high local rane) narcosis. Top up irradiation under ambient condi- tumour rate, already. Tumour regrowth after combined tions or under clamped hypoxia was performed with i.p. treatment was observed in less than 50% of the animals. narcosis (fentanyl, midazolam, medetomidine), as rec- Figure 3 shows data on the 2-, 4- and 8-fold tumour ommended by the university veterinarian department. For regrowth after single and combined treatment with a 10 animals, whose tumours were clamped irradiation was Gy top up dose, exemplarily. In this subset of experi- performed 10 minutes after applying a narrow lace to the ments, five of nine mice were lacking any tumour right hind limb just at the proximal end of the tumour to regrowth 270 days after start of treatment. Analysis of the make the hypoxic radiation conditions as consistent as median time of tumour regrowth after combined treat- possible. Experiments were performed in one run with ment was impaired by an unexpected high rate of local 252 animals. control (figure 3). Therefore, we decided to choose the more complex probit non linear regression analysis. Tumour volumes were scored twice a week, no blinding took place. Follow up was discontinued after 270 days or Figure 4 depicts the extraordinary efficacy of the com- in case of intercurrent death or if tumours had grown to bined treatment by the probit analysis. Irradiation with eight-times the initial tumour volume at the start of treat- graded top up doses from 0 to 44.2 Gy alone resulted in ment. Growth delay and local tumour control were end- local tumour control from 0 to 52% under ambient con- points of the study. All animal experiments were ditions (figure 4a, grey solid line). Addition of lexatumu- accomplished in accordance with the guidelines of the mab after fractionated irradiation alone already caused local authorities (Regional Board Tuebingen, Germany, very high tumour control rates of 85-87%, regardless of appl.no. R4/04) and the German animal welfare regula- the top up dose (p = 0.000006, figure 4a, black solid line). tions. Under clamped bloodflow, treatment with lexatumumab enhanced local tumour control after irradiation with frac- Statistical Analysis tionated irradiation and graded top up doses (0 to 44.2 Statistical analysis was performed as described before. Gy) alone from 0% - 30% (figure 4b, grey solid line) up to In short terms, an exponential regression model was used 43 - 87% (p = 0.00003, figure 4b, black solid line). Statis- to interpolate median tumour regrowth times. Regrowth tical analysis unveiled a highly significant increase of delay was compared by unparametric Kruskal-Wallis tests tumour control rates under both, ambient (p < 0.0001) with Dunn's post tests. Tumour control rates were calcu- and hypoxic (p < 0.0001) conditions (table 1). lated accounting for censored animals as described by Walker and Suit. Data were analysed by a probit non Discussion linear regression analysis. Parameters were estimated Our data prove that the combination of the proapoptotic using the maximum likelihood method. Statistical signif- human antibody lexatumumab with ionizing radiation icance was calculated asymptotically by means of a Hes- has an obvious influence on local tumour control in a sian matrix (STATISTICA 6.0 StatSoft, Hamburg, long-term xenograft model. The effect is evident after irra- Germany). diation with low doses, already. Results It is important to note that these experiments with an ago- Treatment with lexatumumab failed to induce any nistic antibody against TRAIL receptor DR5 corroborate immune reactions of the irradiated skin. No evidence of our recently published data on a high efficacy of a com- acute toxicity was observed. Follow up revealed no signif- bined treatment with another proapoptotic antibody icant differences in frequency of intercurrent deaths after (mapatumumab, anti-DR4) and irradiation. Both models irradiation alone or combined treatment with lexatumu- are in line with in vitro data from our and other labs dem- mab (5.6% vs. 4.6%). onstrating that irradiation acts as a TRAIL sensitizer and not obversely[3,29,30]. Page 3 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:49 http://www.ro-journal.com/content/4/1/49 d5 d1 d7 d10 d18 d32 d46 d81 Photograph tu Figure 2 mumab (0.75 mg/kg; ic showcase of the d 1, 4 an chronological d 8) from day 1(d1 sequence of tumour regression and tumou ) up to day 81 (d81) of treatment r regrowth after i.p. application of lexa- Photographic showcase of the chronological sequence of tumour regression and tumour regrowth after i.p. application of lexatumumab (0.75 mg/kg; d 1, 4 and 8) from day 1(d1) up to day 81 (d81) of treatment. Page 4 of 8 (page number not for citation purposes) Radiation Oncology 2009, 4:49 http://www.ro-journal.com/content/4/1/49 control lexa 10 Gy a 10 Gy a + lexa 0 2040 60270 Follow up [d] Median treatment Figure 3 tumour regrowth times, calculated for two-, four-, and eight-fold tumour size of the initial tumour volume at start of Median tumour regrowth times, calculated for two-, four-, and eight-fold tumour size of the initial tumour vol- ume at start of treatment. Crossbars show 25-75% quartiles for each tumour volume and each treatment. Control; small circle, solid line = animals receiving only i.p. injection with medium, without any further treatment. 10 Gy, square, solid line = fractionated irradiation (3 × 5 Gy) + 10 Gy single top up irradiation. Lexa; triangle, solid line = lexatumumab (0.75 mg/kg body weight, i.p. injection d 1, 4, 8). 10 Gy + lexa; large circle, solid line = fractionated irradiation (3 × 5 Gy) + 10 Gy single top up irradiation and lexatumumab (0.75 mg/kg body weight, i.p. injection d 1, 4, 8). a = Treatment under ambient conditions. This principle diverges from other combined approaches ing a considerable mitochondrial relevance for this syner- where classical chemotherapeutic or other molecular tar- gizing principle[10,39,40]. geted agents act as radiosensitizer. E.g. the synergizing effi- cacy of cisplatin is based on increased oxygenation of The role of radiation induced TRAIL receptor upregulation hypoxic cells and an influence in DNA-repair and cell has been discussed extensively. However, we and others cycle regulation [31-33]. Cetuximab, an antibody against found an only weak or lacking correlation between upreg- epidermal growth factor receptor, seems also to influence ulation and synergism [10,41,42]. Although, other mech- long-term tumour control by affecting DNA damage anisms like cell cycle regulation might play a role . repair[34,35]. It is important to note, that this synergistic principle In contrast to former reports the mitochondrial pathway works under ambient and hypoxic conditions as well. has a strong impact in TRAIL induced apoptosis. Depend- Weinmann et al. demonstrated an undiminished efficacy ing on the cell system applied mitochondrial amplifica- of TRAIL alone under hypoxia in a lymphoma cell tion loops account for its high efficacy[36,37]. In model. Takahashi at al. reported similar observations combination with TRAIL, irradiation increases apoptosis on clonogenic cell kill of A549 cells after treatment with in tumour cells with an impaired mitochondrial pathway. TRAIL and irradiation. However, it remains specula- Furthermore, preirradiation of bcl-2 overexpressing lym- tive why this effect on local tumour control is more pro- phoma cells raises cell death rates after TRAIL receptor nounced under normoxia than under hypoxia. The stimulation. In several tumour cell systems, the proa- known increase of intrinsic radioresistance of hypoxic poptotic molecule Bax was shown to be essential for the cells will be responsible for this reduced susceptibility. combined effect of TRAIL and ionizing radiation suggest- Page 5 of 8 (page number not for citation purposes) relative tumour volume [x-fold tumor size of the initial tumour volume at start of treatment] Radiation Oncology 2009, 4:49 http://www.ro-journal.com/content/4/1/49 a b 1 1 0.9 0.9 0.8 0.88 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 10 20 30 40 50 0 10 20 30 40 50 Dose [Gy] Dose [Gy] Dose-r Figure 4 esponse relation between tumour control probability and top up irradiation dose for Colo205 xenograft tumours Dose-response relation between tumour control probability and top up irradiation dose for Colo205 xenograft tumours. Grey circle, solid grey line = tumours treated with fractionated irradiation (5 × 3 Gy) and graded single top up doses (0-44.2 Gy) alone. Black diamond, solid black line = tumours treated with fractionated irradiation (5 × 3 Gy) and graded single top up doses (0-44.2 Gy) and lexatumumab (0.75 mg/kg body weight, i.p. injection d 1, 4, 8) a: under ambient conditions, b: under hypoxic conditions. Dashed lines represent the 95% confidence level. The strong request on the development of personalized an accurate identification of patient collectives who bene- targeted therapies has amazingly changed the general fit from a given treatment. Therefore, a specific subset of approach to cancer treatment. In contrast to cytostatic marker molecules should be identified for each targeted drugs being prescribed on base of classical features as drug [46-48]. TNM classification and histology, targeted drugs require Conclusion Table 1: Results of the probit regression analysis comparing The here presented data provide evidence that the combi- combined treatment (lexatumumab (= lexa, 0.75 mg/kg) and nation of apoptosis inducing antibodies with irradiation irradiation (= RT, 5 × 3 Gy and graded top up doses 0-44.2 Gy) strongly increases long-term tumour control. Since with irradiation alone murine long-term control experiments are the only cur- const. B0 RT-dose (B1) lexa (B2) rently accepted functional approach to simulate the effi- cacy of radiation based treatments the given data are an normoxia optimal scientific base for subsequent clinical trials. Parameter (MLE*) - 1.729 0.028 2.062 Competing interests SE 0.386 0.012 0.343 The authors declare that they have no competing interests. p-value 0.0002 0.0294 <0.0001 Authors' contributions clamped hypoxia PM conceived and drafted the manuscript. DJ and SS car- ried out the animal experiments to the same portion. WB Parameter (MLE) - 2.424 0.035 2.097 SE 0.489 0.013 0.396 performed the statistical analysis. MN participated in the p-value <0.0001 0.0147 <0.0001 statistical analysis and in the drafting of the manuscript. CB contributed to interpretation of the data and critically Regression constant B0 reviewed the article. All authors read and approved the * Maximum likelihood estimate final manuscript. § Standard error Page 6 of 8 (page number not for citation purposes) p Radiation Oncology 2009, 4:49 http://www.ro-journal.com/content/4/1/49 tumors or lymphomas.ASCO Annual meeting. Orlando, Acknowledgements Florida, USA, . J Clin Oncol 2008. May 20 suppl; abstr 3537 We thank Human Genome Sciences, Inc. for providing lexatumumab and 15. Sikic BI, Wakelee H, von Mehren M, Lewis NL, Plummer ER, Calvert Dirk Schiller, University of Tübingen, for providing the pictures on tumour AH, Fox NL, Kumm EA, Jones DF, Burris HA: A phase 1b study to growth after treatment with lexatumumab. In addition, we like to thank assess the safety of lexatumumab, a human monoclonal anti- body that activates TRAIL-R2, in combination with gemcit- Katrin Stasch and Stefan Ablasser for technical assistance. This work was abine, pemetrexed, doxorubicin or FOLFIRI. Abstract, 2007. supported by a grant from the Federal Ministry of Education and Research Proceedings of the American Society of Clinical Oncology 25:14006. (Fö: 1456-00) to CB and VJ and by the 'Deutsche Krebshilfe' (Grants10- 16. Tolcher AW, Mita M, Meropol NJ, von Mehren M, Patnaik A, Padavic 1764 Be1 and 10-2220 Be4) to CB, PM and WB. 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Mrozek A, Petrowsky H, Sturm I, Kraus J, Hermann S, Hauptmann S, Lorenz M, Dorken B, Daniel PT: Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma Publish with Bio Med Central and every with low microsatellite instability. Cell Death Differ 2003, scientist can read your work free of charge 10:461-467. 48. Kallioniemi A: CGH microarrays and cancer. CurrOpin Biotechnol "BioMed Central will be the most significant development for 2008, 19:36-40. disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 8 of 8 (page number not for citation purposes)
Radiation Oncology – Springer Journals
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